tbuckley/cabot-search huggingface dataset:
Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
Authors: Chunling Hu, Anil Belur Nagaraj, Hermela Shimelis, Gemma Montalban, Kun Y. Lee, Huaizhi Huang, Carolyn A. Lumby, Jie Na, Lisa R. Susswein, Maegan E. Roberts, Megan L. Marshall, Susan Hiraki, Holly LaDuca, Elizabeth Chao, Amal Yussuf, Tina Pesaran, Susan L. Neuhausen, Christopher A. Haiman, Peter Kraft, Sara Lindstrom, Julie R. Palmer, Lauren R. Teras, Celine M. Vachon, Song Yao, Irene Ong, Katherine L. Nathanson, Jeffrey N. Weitzel, Nicholas Boddicker, Rohan Gnanaolivu, Eric C. Polley, Georges Mer, Gaofeng Cui, Rachid Karam, Marcy E. Richardson, Susan M. Domchek, Siddhartha Yadav, Kathleen S. Hruska, Jill Dolinsky, S. John Weroha, Steven N. Hart, Jacques Simard, Jean Yves Masson, Yuan-Ping Pang, Fergus J. Couch
Journal: Cancer Research (2023)

Abstract Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C−/− cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. Significance: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.
Biosimilars for the Treatment of Psoriasis
Authors: Duc Binh Phan, Sarah Elyoussfi, Michael Stevenson, Mark Lunt, Richard B. Warren, Zenas Z. N. Yiu
Journal: JAMA Dermatology (2023)

Importance Biosimilars have the potential to reduce costs for the management of moderate-to-severe psoriasis compared with originators. However, the extrapolation of evidence enables the approval of a biosimilar for use in indications held by the originator without directly being studied in clinical trials. Thus, biosimilars can be approved for psoriasis based on extrapolated evidence from other diseases. The availability of evidence for the effectiveness and safety of biosimilars for the treatment of psoriasis is therefore unclear. Objective To compare the efficacy/effectiveness and safety of biosimilars with originator biologics for the treatment of patients with psoriasis. Evidence Review MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, and The European Union Clinical Trials Register were searched in August 2022. Eligible studies were appraised using the Cochrane Risk of Bias 2 and ROBINS-I tools. All analyses were conducted from September 2022 to November 2022. Findings Fourteen trials (10 adalimumab, 2 etanercept, 1 infliximab, and 1 ustekinumab) and 3 cohort studies (1 adalimumab, 1 etanercept, 1 infliximab and etanercept) were included. Twelve trials compared biosimilars with originators in originator-naive patients (starters), and 11 trials compared switching from originator to biosimilar (switchers) with continuous originator treatments. There was no clinically or statistically significant difference in rates of achieving 75% improvement in Psoriasis Area and Severity Index scores and risks of adverse events (AEs) at week 16 and week 52 between the comparators. Two cohort studies showed no difference in effectiveness and safety outcomes between originators and biosimilars, whereas 1 study reported more AEs in patients who switched to biosimilars of adalimumab at 12 months. Three trials showed low risk of bias, whereas 11 trials had moderate risk of bias. All cohort studies had moderate to high risk of bias. Conclusions and Relevance In this systematic review, there was no clinically or statistically significant difference in the efficacy and safety between biosimilars and originators for the treatment of patients with psoriasis. Most of the available evidence was based on randomized clinical trials, although high-quality real-world evidence was lacking. Future studies are needed to examine the long-term effectiveness and safety of biosimilars for the treatment of patients with psoriasis.
Early Palliative Care Consultation Before High-risk Surgery
Authors: Barbara Haas, Gordon D. Rubenfeld
Journal: JAMA Network Open (2023)

Rebecca A. Aslakson, MD; Elizabeth Rickerson, MD; Bridget Fahy, MD; Brittany Waterman, MD; Rachel Siden, MA; Kathryn Colborn, PhD; Shelby Smith, MS; Mae Verano, BA; Isaac Lira, BS; Caroline Hollahan, BS; Amn Siddiqi, MBBS; Kemba Johnson, CCMA; Shivani Chandrashekaran, BS; Elizabeth Harris, BS; Richard Nudotor, MD; Joshua Baker, BS; Shireen N. Heidari, MD; George Poultsides, MD; Alison M. Conca-Cheng, MD; Allyson Cook Chapman, MD; Anna Sophia Lessios, MD; Laura M. Holdsworth, PhD; Jillian Gustin, MD; Aslam Ejaz, MD; Timothy Pawlik, MD; Judi Miller, AIA; Arden M. Morris, MD; James A. Tulsky, MD; Karl Lorenz, MD; Jennifer S. Temel, MD; Thomas J. Smith, MD; Fabian Johnston, MD
Late-onset Cognitive Impairment and Modifiable Risk Factors in Adult Childhood Cancer Survivors
Authors: Nicholas S. Phillips, Kayla L. Stratton, AnnaLynn M. Williams, Tim Ahles, Kirsten K. Ness, Harvey Jay Cohen, Kim Edelstein, Yutaka Yasui, Kevin Oeffinger, Eric J. Chow, Rebecca M. Howell, Leslie L. Robison, Gregory T. Armstrong, Wendy M. Leisenring, Kevin R. Krull
Journal: JAMA Network Open (2023)

Long-term survivors of childhood cancer may be at elevated risk for new neurocognitive impairment and decline as they age into adulthood.
A non-coding variant linked to metabolic obesity with normal weight affects actin remodelling in subcutaneous adipocytes
Authors: Viktoria Glunk, Samantha Laber, Nasa Sinnott-Armstrong, Debora R Sobreira, Sophie M Strobel, Thiago M Batista, Phil Kubitz, Bahareh Nemati Moud, Hannah Ebert, Yi Huang, Beate Brandl, Garrett Garbo, Julius Honecker, David R Stirling, Nezar Abdennur, Virtu Calabuig-Navarro, Thomas Skurk, Soeren Ocvirk, Kerstin Stemmer, Beth A Cimini, Anne E Carpenter, Simon N Dankel, Cecilia M Lindgren, Hans Hauner, Marcelo A Nobrega, Melina Claussnitzer
Journal: Nature Metabolism (2023)
Table Heading Error and Additional Clarifications
Journal: JAMA Network Open (2023)

was an error in a column heading in the Table ."March 2019" should be "March 2020."In addition, in response to a reader asking for clarifications, the editors have added the following: the unit of analysis "initiation" has been defined as "admission to either inpatient or outpatient treatment programs;" the number of treatment initiations has been added ("237 835 before imputation and 247 566 after imputation"); and totals have been added to the eTables in the Supplement. 1 None of the findings, interpretations, or conclusions are affected by this correction and these clarifications.
When I use a word . . . Commercial clinical trials
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

A new report on the conduct of commercially sponsored clinical trials of new medications has just been published. It contains 27 recommendations. The UK government has welcomed all of them, and has promised to fund five. Important features of such trials that are not mentioned in the report include methods for improving and measuring participant adherence to an intervention and methods for detecting harms.
Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation
Authors: O. García-Nicolás, A. Godel, G. Zimmer, A. Summerfield
Journal: Cellular and Molecular Immunology (2023)

Abstract Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent or unregulated proinflammatory cytokine responses are associated with severe disease outcomes. Previous work suggested that monocyte-derived macrophages (MDMs) are resistant and unresponsive to SARS-CoV-2 infection. Here, we demonstrate that upon phagocytosis of SARS-CoV-2-infected cells, MDMs are activated and secrete IL-6 and TNF. Importantly, activated MDMs in turn mediate strong activation of plasmacytoid dendritic cells (pDCs), leading to the secretion of high levels of IFN-α and TNF. Furthermore, pDC activation promoted IL-6 production by MDMs. This kind of pDC activation was dependent on direct integrin-mediated cell‒cell contacts and involved stimulation of the TLR7 and STING signaling pathways. Overall, the present study describes a novel and potent pathway of pDC activation that is linked to the macrophage-mediated clearance of infected cells. These findings suggest that a high infection rate by SARS-CoV-2 may lead to exaggerated cytokine responses, which may contribute to tissue damage and severe disease.
Patterns of Tumor-Infiltrating Lymphocytes Used to Distinguish Primary Cutaneous Squamous Cell Carcinomas That Metastasize
Authors: Sepideh Ashrafzadeh, Ruth K. Foreman, Sara Kalra, Anna Mandinova, Maryam M. Asgari
Journal: JAMA Dermatology (2023)

This case-control study examines the type, location, and density of tumor-infiltrating lymphocytes in adult patients with vs without metastatic cutaneous squamous cell carcinoma.
Biosimilars for the Treatment of Psoriasis—A Systematic Review of Clinical Trials and Observational Studies
Authors: Luigi Naldi, Antonio Addis
Journal: JAMA Dermatology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Food allergy is associated with increased risk of developing psychological disorders: A nationwide study of 603,257 Israelis
Authors: Shay Nemet, Keren Mahlab‐Guri, Daniel Elbirt, Shira Bezalel‐Rosenberg, Ilan Asher, Aviv Talmon, Limor Rubin, Yaarit Ribak, Ruslan Sergienko, Yuval Tal, Oded Shamriz
Journal: Allergy (2023)
Machine Learning–Based Treatment Allocation for Recurrent Hepatocellular Carcinoma
Authors: Yasuyuki Shigematsu, Kentaro Inamura
Journal: JAMA Surgery (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Advances in systemic therapies for triple negative breast cancer
Authors: Roberto A Leon-Ferre, Matthew P Goetz
Journal: BMJ (2023)

Triple negative breast cancer (TNBC) continues to be the subtype of breast cancer with the highest rates of recurrence and mortality. The lack of expression of targetable proteins such as the estrogen receptor and absence of HER2 amplification have made relying on cytotoxic chemotherapy necessary for decades. In the operable setting, efforts to improve outcomes have focused on escalation of systemic therapy and a shift toward preoperative delivery followed by a response adapted approach to postoperative systemic therapy. An improved understanding of tumor biology has resulted in the identification of subsets of patients with specific molecular features, leading to testing and approval of multiple new targeted therapies for this disease. Furthermore, advances in drug development have led to the approval of antibody-drug conjugates that are redefining classification schemes for breast cancer. This review focuses on the modern management of TNBC, with particular focus on recent updates in the treatment of operable disease, and an overview of the most recent promising advances in the therapeutic landscape of metastatic disease. It discusses the practical challenges and unanswered questions resulting from the approval of neoadjuvant immunotherapy and shares an approach in the clinic on topics for which evidence is lacking. In addition, it provides a glimpse into the future, highlighting challenges and opportunities for biomarker based right-sizing of preoperative therapy, refining evaluation of response to preoperative therapy after surgery, early diagnosis and detection of relapse, and areas of needed research for metastatic TNBC.
New Paradigm for Activity Restriction Following Urogynecologic Surgery
Authors: Marisa C. Vega, Cecile A. Ferrando
Journal: JAMA Surgery (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Surrogate and modified endpoints for immunotherapy in advanced hepatocellular carcinoma
Authors: Mir Lim, Maishara Muquith, Bernadette Miramontes, Chieh-Ju Lee, Magdalena Espinoza, Yi-Hsiang Huang, David Hsiehchen
Journal: Hepatology (2023)

Background and Aims: Immunotherapies have altered the treatment paradigm in HCC. Surrogate and modified endpoints are used to assess early success in clinical studies and guide clinical practice. We sought to determine whether surrogate endpoints and modifications to the conventional criteria for tumor response (RECIST), including modified RECIST (mRECIST) and immune-modified RECIST (imRECIST), are valid measures to predict overall survival (OS) in HCC treated with immunotherapies. Approach and Results: We performed an individual-level post hoc analysis of patients treated with atezolizumab and bevacizumab in the IMbrave150 trial (N = 279) and a cross-sectional analysis of a multicenter real-world patient cohort treated with immunotherapy (N = 328). Landmark analyses showed that objective response rates by RECIST were associated with greater OS including among Child-Pugh A and B patients and among patients treated with immunotherapies in the first- or second-line setting (IMbrave150: HR 0.24, 95% CI, 0.17–0.33; RW: HR 0.25, 95% CI, 0.15–0.43). Objective response rates by mRECIST or imRECIST were not associated with the greater predictive power of OS benefit (mRECIST: HR 0.30, 95% CI, 0.22–0.42; imRECIST: HR 0.36, 95% CI, 0.30–0.51). Progression-free survival determined by RECIST was only moderately correlated with OS, and this association was not improved using mRECIST or imRECIST. Conclusions: Our results clarify the utility of surrogate and modified endpoints in HCC treated with immunotherapies and support the use of RECIST objective response rates as an appropriate signal-finding measure for the evaluation of emerging treatments. Contrary to their intended purpose, mRECIST and imRECIST did not provide meaningful improvements in predicting OS benefits.
Continuation of therapeutic dose heparin for critically ill patients with COVID-19
Authors: Charlotte A. Bradbury, Patrick R. Lawler, Bryan J. McVerry, Ryan Zarychanski, Farah Al-Beidh, Derek C. Angus, Yaseen M. Arabi, Diptesh Aryal, Djillali Annane, Abi Beane, Lindsay R. Berry, Scott Berry, Zahra Bhimani, Shailesh Bihari, Marc J. M. Bonten, Charlotte A. Bradbury, Frank M. Brunkhorst, Meredith Buxton, Adrian Buzgau, Marc Carrier, Allen C. Cheng, Matthew Cove, Lennie P. G. Derde, Michelle A. Detry, Lise J. Estcourt, Dean A. Fergusson, Mark Fitzgerald, Robert A. Fowler, Timothy D. Girard, Ewan C. Goligher, Herman Goossens, Anthony C. Gordon, Cameron Green, Rashan Haniffa, Alisa M. Higgins, Thomas Hills, David T. Huang, Christopher M. Horvat, Beverley J. Hunt, Nao Ichihara, Devachandran Jayakumar, Anand Kumar, Michael A. Laffan, Francois Lamontagne, Patrick R. Lawler, Helen L. Leavis, Roger J. Lewis, Kelsey M. Linstrum, Edward Litton, Elizabeth Lorenzi, Sylvain A. Lother, John C. Marshall, Colin J. McArthur, Daniel F. McAuley, Anna McGlothlin, Shay P. McGuinness, Saskia Middeldorp, Srinivas Murthy, Zoe McQuilten, Bryan J. McVerry, Paul R. Mouncey, Matthew D. Neal, Alistair D. Nichol, Rachael L. Parke, Jane C. Parker, Asad Patanwala, Luis Reyes, Kathryn M. Rowan, Hiroki Saito, Marlene S. Santos, Christina T. Saunders, Roger E. G. Schutgens, Ary Serpa-Neto, Christopher W. Seymour, Manu Shankar-Hari, Vanessa Singh, Simon J. Stanworth, Timo Tolppa, Alexis F. Turgeon, Anne M. Turner, Wilma van Bentum-Puijk, Frank L. van de Veerdonk, Steve A. Webb
Journal: Intensive Care Medicine (2023)
Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms
Authors: Joeffre Braga, Mariel Lepra, Stephen J. Kish, Pablo. M. Rusjan, Zahra Nasser, Natasha Verhoeff, Neil Vasdev, Michael Bagby, Isabelle Boileau, M. Ishrat Husain, Nathan Kolla, Armando Garcia, Thomas Chao, Romina Mizrahi, Khunsa Faiz, Erica L. Vieira, Jeffrey H. Meyer
Journal: JAMA Psychiatry (2023)

Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition.To determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC.This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET.The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function.The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, -0.53; 95% CI, -0.79 to -0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68).In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.